Background and Purpose - Regular physical activity (PA) is an important recommendation for stroke prevention. We compared the associations of self-reported PA with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Methods - REGARDS recruited 30 239 US blacks (42%) and whites, aged ≥45 years with follow-up every 6 months for stroke events. Excluding those with prior stroke, analysis involved 27 348 participants who reported their frequency of moderate to vigorous intensity PA at baseline according to 3 categories: none (physical inactivity), 1 to 3×, and ≥4× per week. Stroke and transient ischemic attack cases were identified during an average of 5.7 years of follow-up. Cox proportional hazards models were constructed to examine whether self-reported PA was associated with risk of incident stroke. Results - Physical inactivity was reported by 33% of participants and was associated with a hazard ratio of 1.20 (95% confidence intervals, 1.02-1.42; P=0.035). Adjustment for demographic and socioeconomic factors did not affect hazard ratio, but further adjustment for traditional stroke risk factors (diabetes mellitus, hypertension, body mass index, alcohol use, and smoking) partially attenuated this risk (hazard ratio, 1.14 [0.95-1.37]; P=0.17). There was no significant association between PA frequency and risk of stroke by sex groups, although there was a trend toward increased risk for men reporting PA 0 to 3× a week compared with ≥4× a week. Conclusions - Self-reported low PA frequency is associated with increased risk of incident stroke. Any effect of PA is likely to be mediated through reducing traditional risk factors. © 2013 American Heart Association, Inc.